Total synthesis of the utero-evacuant substance d,l-zoapatanol

ABSTRACT

A method for the synthesis of racemic 2S*,3R*-6E-(2&#34;-hydroxyethylidene)-2-methyl-2-(4&#39;,8&#39;-dimethyl-5&#39;-oxo-7&#39;-nonenyl)-oxepan-3-ol is described. The naturally occurring product, 2S,3R-6E-(2&#34;-hydroxyethylidene)-2-methyl-2-(4&#39;,8&#39;-dimethyl-5&#39;-oxo-7&#39;-nonenyl)-oxepan-3-ol, is one of the active components of the zoapatle plant.

The zoapatle plant is a bush about two meters high that grows wild inMexico. Botanically, it is known as Montanoa tomentosa according toCervantes, Fam. Compositae, Tribe Heliantheae; another variety of thespecies is Montanoa floribunda. The plant is described in great detailin Las Plantas Medicinales de Mexico, Third Edition, Ediciones Botas(1944).

The plant has been used for centuries in the form of a "tea" or othercrude aqueous preparations primarily as a labor inducer or mensesinducer for women. Its use as a utero-evacuant has been documented inthe literature.

In U.S. Pat. No. 4,086,358, a method is described for the isolation ofthe active ingredients in the zoapatle plant. One of the activeingredients is2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.This compound, referred to as zoapatanol, has the following structuralformula: ##STR1##

The present invention relates to a method for the total synthesis of2S*,3R*-6E-(2-hydroxyethylidene)-2-methyl-2-(4',8'-dimethyl-5'-oxo-7'-nonenyl)-oxepan-3-oland2S*,3R*-6Z-(2-hydroxyethylidene)-2-methyl-2-(4',8'-dimethyl-5'-oxo-7'-nonenyl)-oxepan-3-ol.##STR2##

The asterisk in the name (e.g. 2S*,3R*) indicates the racemic nature ofthe compound and thus refers to the relative configuration of the chiralcenters. The lettering of the appropriate positions corresponds to thatof the naturally occurring optical isomer 28 (e.g. 2S,3R).

Many of the intermediates employed in the synthesis of zoapatanol arenovel compounds and are included as part of the invention.

The synthesis is comprised of several steps which are summarized in thefollowing schematic diagram: ##STR3##

In the above diagram, the symbols Ph, p-TsOH, Ac, EtOH, DMF, Et and Bustand for phenyl, p-toluenesulfonic acid, acetyl, ethanol,dimethylformamide, ethyl and butyl respectively and R is at-butyldiphenylsilyl group.

The starting material in the synthesis is3-benzyloxy-2-methyl-2-(4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl-oxepan-6-one(1). As seen from the diagram in the first step in the synthesis, theketone (1) is converted to a ketal (2) by reaction with ethylene glycol.The reaction is carried out at elevated temperatures, preferably thereflux temperature of the solvent in the presence of a catalyst such as,for example p-toluenesulfonic acid. Suitable solvents which can beemployed include benzene and toluene. The compound (2) is collected andpurified by techniques known to those skilled in the art and thenconverted to an alcohol (3) by reaction with sodium in liquid ammonia.The reaction is preferably carried out in an inert atmosphere such asargon or nitrogen, for example. The alcohol (3) is separated from thereaction mixture, purified by techniques known to those skilled in theart and then converted to the corresponding t-butyldiphenylsilyloxyderivative (4) by reaction with t-butyldiphenylsilyl chloride in asuitable solvent such as dimethylformamide or benzene in the presence ofimidazole. The reaction is preferably carried out at the refluxtemperature of the solvent. The tetrahydropyranyl and the ketalprotecting groups are removed during the reaction; the hydroxyl group isreprotected by reacting the t-butyldiphenylsilyloxy derivative withdihydropyran. The reaction is preferably carried out in a solvent suchas ether or methylene chloride at room temperature and in an inertatmosphere such as nitrogen. p-Toluenesulfonic acid or camphorsulfonicacid is added as a catalyst. The tetrahydropyranyl ketone (5) uponreaction with triethylphosphonoacetate in the presence of an alkalimetal hydride such as sodium hydride or potassium hydride, is convertedto a mixture of carboethoxymethylidene double bond isomers (6 and 7).The reaction is carried out in a suitable solvent such as benzene in thepresence of sodium hydride. Temperatures between room temperature andabout 100° C. may be employed and the reaction is preferably carried outin an inert atmosphere such as nitrogen or argon. The mixture ispurified by techniques known to those skilled in the art and is thenconverted to a mixture of alcohols (8 and 9) by reaction with a reducingagent such as lithium aluminum hydride. The reaction is preferablycarried out in a solvent such as diethyl ether or tetrahydrofuran at thereflux temperature of the solvent in an inert atmosphere such asnitrogen. The diols (8 and 9) are separated by chromatography usingsilica gel as the adsorbent in hexane. The diol (8) is then converted tothe t-butyldiphenylsiloxy derivative (10) by reaction witht-butyldiphenylsilyl chloride in dimethylformamide in the presence ofimidazole. The reaction is preferably carried out in a suitable solventat room temperature in an inert atmosphere. The t-butyldiphenylsilylderivative (10) is separated and purified by techniques known to thoseskilled in the art. The tetrahydropyranyl group is then removed byreaction of the t-butyldiphenylsilyl derivative (10) with an organicacid such as acetic acid, for example, to form the alcohol (11) which isthen oxidized to the corresponding aldehyde (12) by reaction with anoxidizing agent such as chromium trioxide/pyridine in a suitable solventsuch as methylene chloride. The side chain in the molecule is extendedby reacting the aldehyde (12) with an acetylenic Grignard reagent suchas that prepared from 3-methyl-1-butyne. The resulting acetyleniccompound (13) is then converted to the olefinic compound (14) byreduction with lithium aluminum hydride. The reduction is preferablycarried out in an anhydrous solvent such as tetrahydrofuran or ether inan inert atmosphere such as nitrogen or argon. The allylic hydroxylgroup in the side chain is converted to a keto group by reaction with anoxidizing agent such as chromium trioxide/pyridine in methylene chlorideor with manganese dioxide in methylene chloride or chloroform. Theunsaturated ketone (15) is converted to a β,γ unsaturated ketone (16) byreaction with potassium-t-butoxide in butanol followed by treatment withan organic acid such as acetic acid. The reaction is preferably carriedout at room temperature in an inert atmosphere such as nitrogen, forexample. The β,γ unsaturated ketone (16) is then reduced to the alcohol(17) by reaction with a suitable reducing agent such as sodiumborohydride in a suitable solvent such as ethanol. The alcohol (17) isthen converted to the corresponding tetrahydropyranyl derivative (18) byreaction with dihydropyran in the presence of p-toluenesulfonic acid ina suitable solvent such as ether. The tetrahydropyranyl derivative (18)is then converted to a mixture of diols (19 and 20) by reaction withtetrabutylammonium fluoride in a suitable solvent such astetrahydrofuran.

The diols are separated by methods known to those skilled in the art.Column chromatography on an adsorbent material such as silica gel is apreferred method. The diols (19,Z isomer and 20,E isomer) each containall of the 20 carbon atoms present in zoapatanol (E-isomer). A four stepsequence converts the diols (19 and 20) to racemic zoapatanol (28) andto the racemic Z isomer (24).

The first step in the synthesis of the naturally occurring isomer (28)from the diol (20) involves the preparation of the corresponding diester(25). The diester (25) is prepared by conventional means from a loweralkyl anhydride or alkanoyl halide such as, for example, aceticanhydride or acetyl chloride in the presence of a base such as pyridine.The tetrahydropyranyl protecting group is removed by treating thediester (25) with an organic acid such as acetic acid, p-toluenesulfonicacid or camphorsulfonic acid in a suitable solvent mixture such astetrahydrofuran-water, for example. The alcohol (26) which forms is thenoxidized to the corresponding ketone (27) with an oxidizing agent suchas chromium trioxide/pyridine. Reaction of the ketone (27) withtetrabutylammonium hydroxide in a suitable solvent such as methanolyields racemic zoapatanol. The same series of reactions when carried outon the isomeric diol (19) leads to the Z isomer (24).

As employed herein, R is a t-butyldiphenylsilyl group, R₁ is a loweralkanoyl group having 2-5 carbon atoms such as an acetyl, propionyl orbutyryl group and R₂ is selected from the group consisting of benzyl,p-nitrobenzyl and p-methylbenzyl.

The following describes the invention in greater particularity and isintended to be a way of illustrating but not limiting the invention.

EXAMPLE 1(2S*,3R*)-3-Benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepan-6-one(1)

A solution of pyridine (5.4 g, 0.0686 mol) and chromium trioxide (3.4 g,0.0343 mol) in methylene chloride (150 ml) at 23° in a nitrogenatmosphere is stirred for 45 minutes. The mixture is cooled to -10° andcelite (20 g) is added followed by the alcohol2S*,3R*-3-benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepan-6-ol(2.4 g, 0.0057 mol) in methylene chloride (50 ml). After stirring for 2hours at 0°, the mixture is filtered and the celite cake is washed withmethylene chloride (10×50 ml). The filtrate and the washings arecombined and washed with saturated sodium bicarbonate (2×100 ml), dried(MgSO₄) and evaporated in vacuo. The crude product (2.8 g) ischromatographed on SilicAR CC-7 (40 g, Mallinckrodt) in hexane. Elutionwith 10% ethyl acetate/hexane gives (2S*,3R*)-3-benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepan-6-oneas a clear colorless oil (2.1 g, 88%): nmr (CDCl₃)δ 1.00 (d, J=6 Hz, 3H,--CH--CH₃), 1.30 (s, 3H, CH₃), 2.60 (m, 2H, --CO--CH₂ --CH₂ --), 3.98(m, 2H, --O--CH₂ --CO--), 4.50 (d of d, J=10 Hz, 2H, --O--CH₂ Ph), 4.60(broad s, 1H, --O--CH--O--), 7.2 (s, 5H, aromatic).

EXAMPLE 2(2S*,3R*)-3-Benzyloxy-6,6-ethylenedioxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepane(2)

A mixture of(2S*,3R*)-3-benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepan-6-one(2.1 g, 0.005 mol), ethylene glycol (10 ml) and p-toluenesulfonic acid(350 mg) in benzene (75 ml) is refluxed for 20 hours using a Dean-Starkapparatus. The solution is cooled and diluted with water (150 ml) andether (150 ml). The organic layer is separated and the aqueous layer isextracted with ether (2×250 ml). The combined organic layers are washedwith saturated sodium bicarbonate solution (2×50 ml), saturated sodiumchloride solution and dried (MgSO₄). The solvents are removed at reducedpressure and the crude product (2.7 g) is chromatographed on SilicARCC-7 (50 g, Mallinckrodt) in hexane. Elution with 2-20% EtOAc/hexanegives(2S*,3R*)-3-benzyloxy-6,6-ethylenedioxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy-pentyl]-oxepane(0.215 g); nmr (CDCl₃)δ 3.35 (m, 7H, ##STR4## 3.9 (s, 4H, ketal), 4.4(m, 3H, ##STR5## --O--CH₂ --Ph), 7.25 (s, 5H, aromatic).

EXAMPLE 3(2S*,3R*)-6,6-Ethylenedioxy-3-hydroxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepane(3)

t-Butyl alcohol (0.222 g, 0.003 mol) is added to a freshly distilledsolution of ammonia (12 ml) cooled to -78° in an argon atmosphere. Thecooling bath is removed and(2S*,3R*)-3-benzyloxy-6,6-ethylenedioxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)pentyl]-oxepane(0.215 g, 0.000465 mol) in tetrahydrofuran (3 ml) is added. Freshly cutsodium metal (0.024 g, 0.001 mol) is added in small pieces at -33° C.The resulting blue solution is stirred for 0.25 hours and quenched byadding ether (20 ml) followed by water (25 ml). The ammonia isevaporated at 23° C. and the ether layer is separated. The water phaseis extracted with ether (3×25 ml). The ether phases are combined, washedwith a saturated sodium chloride solution, dried (MgSO₄) and the solventis removed under reduced pressure to give a crude yellow oil (0.210 g).This material is chromatographed on SilicAR CC-7 (4 g, Mallinckrodt) inhexane. Elution with 2-25% EtOAc/hexane gives(2S*,3R*)-6,6-ethylenedioxy-3-hydroxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepaneas a clear oil (0.170 g): ir (neat) 3335 cm⁻¹ (--OH).

EXAMPLE 4(2S*,3R*)-3-t-Butyldiphenylsilyloxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-oxepan-6-one(4)

(2S*,3R*)-6,6-Ethylenedioxy-3-hydroxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepane(0.150 g, 0.004 mol) is added to a suspension of sodium hydride (0.038g, 0.0008 mol, of a 50% mineral oil dispersion freshly washed withhexane and benzene) in benzene (2 ml) at 23° C. in a nitrogenatmosphere. The mixture is stirred for 1 hour,t-butyldiphenylsilychloride (0.22 g, 0.0008 mol) in benzene (0.5 ml) isadded and the mixture is heated to reflux at 80° C. The mixture isrefluxed for 3 days then cooled to 23° C. and washed with a saturatedsodium bicarbonate solution. The aqueous phase is extracted with ether(2×25 ml). The organic layers are combined, dried (MgSO₄) and thesolvents are removed at reduced pressure to give 0.205 g of crudeproduct. The crude product is chromatographed on SilicAR CC-7 (3.0 g,Mallinckrodt) in hexane. Elution with 10% ethyl acetate gives(2S*,3R*)-3-t-butyldiphenylsilyloxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-oxepan-6-one(0.122 g): nmr (CDCl₃)δ 1.1 (s, 9H, t-butyl), 3.4 (m, 3H, ##STR6## 4.0(m, 2H, ##STR7## 7.5 (m, 10H, aromatic).

EXAMPLE 5(2S*,3R*)-3-t-Butyldiphenylsilyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepan-6-one(5)

A mixture of the alcohol(2S*,3R*)-3-t-butyldiphenylsilyloxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-oxepan-6-one(0.11 g, 0.000228 mol), dihydropyran (0.038 g, 0.000456 mol) andp-toluenesulfonic acid (3 crystals) in anhydrous ether (3 ml) is stirredat 23° C. under a nitrogen atmosphere for 18 hours. The mixture isdiluted with ether (10 ml), washed with saturated sodium bicarbonate,water and saturated sodium chloride, dried (MgSO₄) and evaporated underreduced pressure to give the crude product. The crude product ischromatographed on silica silicAR CC-7 (2 g, Mallinckrodt) in hexane.Elution with ethyl acetate/hexane gives(2S*,3R*)-3-t-butyldiphenylsilyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepan-6-oneas a colorless oil (0.105 g): nmr (CDCl₃)δ 2.35 (t, 2H, ##STR8## 3.35(m, 7H, ##STR9## 4.5 (s, 1H, ##STR10##

EXAMPLE 6(2S*,3R*)-3-t-Butyldiphenylsilyloxy-6-(2'-carboethoxymethylidene)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepane(6) and(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-carboethoxymethyl)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepene(7)

Triethylphosphonoacetate (125 mg, 0.557 mmole) in benzene (3 ml) isadded to a suspension of sodium hydride (27 mg, 0.557 mmole, of a 50%mineral oil dispersion freshly washed with hexane and benzene) inbenzene (2 ml) in a nitrogen atmosphere. The mixture is heated to 70° C.and stirred for 15 minutes. The mixture is then cooled to 25° C. and(2S*,3R*)-3-t-butyldiphenylsilyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepan-6-one(105 mg, 0.186 mmole) in benzene is added. The mixture is heated to 70°C. and stirred for 1 hour. The reaction mixture is then cooled to 25° C.and diluted with ether (10 ml) and quenched with water. The mixture ispoured into pH 7 phosphate buffer (25 ml) and extracted with ether (5×25ml). The organic layers are combined, dried (MgSO₄) and evaporated togive 121 mg of a yellow oil. This material is chromatographed on SilicARCC-7 (2 g, Mallinckrodt) in hexane. Elution with 25% ethylacetate/hexane gives 85 mg of a colorless oil whose nmr indicates it tobe a mixture of(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-carboethoxymethylidene)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepaneand(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-carboethoxymethyl)-2-methyl-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)pentyl]-6-oxepene:nmr (CDCl₃)δ 5.5 (s, 1H, >C═CH-- ##STR11## 5.59 (s, 1H, ##STR12##

EXAMPLE 7(2S*,3R*)-3-t-Butyldiphenylsilyloxy-6-(2'-hydroxyethylidene)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepane(8) and(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-hydroxyethyl)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepene(9)

A solution of the mixture of(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-carboethoxymethylidene)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepaneand(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-carboethoxymethyl)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepene(85 mg, 0.134 mmol) in Et₂ O (2 ml) is added dropwise to a suspension oflithium aluminum hydride (13 mg, 0.33 mmol) in ether (1 ml) in anitrogen atmosphere and refluxed for 1 hour. The reaction mixture isthen cooled at 25° C. and quenching is accomplished by addition of wetether (5 ml). The mixture is diluted with saturated ammonium chloridesolution and extracted with ether (5×20 ml). The ether phases arecombined, dried (MgSO₄) and evaporated in vacuo to give 75 mg of ayellow oil. This material is chromatographed on SilicAR CC-7 (1.8 g,Mallinckrodt) in hexane. Elution with 5% ethyl acetate/hexane gives(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'hydroxyethyl)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepene(33 mg): nmr (CDCl₃)δ 1.05 (s, 9H, -t-butyl), 3.45 (m, 7H, ##STR13##--CH₂ --CH₂ --OH, ##STR14## 4.55 (s, 1H, ##STR15## 5.95 (s, 1H,##STR16## 7.5 (m, 10H, aromatic). Further elution with 7% ethylacetate/hexane gives a mixture of(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-hydroxyethylidene)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepaneand(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-hydroxyethyl)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepene(25 mg) and(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-hydroxyethyl)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepene(13 mg) nmr (CDCl₃) δ 5.35 (s, 1H, >C═CH--CH₂ --OH), 3.5 (m, 9H,##STR17##

EXAMPLE 8(2S*,3R*)-3-t-Butyldiphenylsilyloxy-6-(2'-t-butyldiphenylsilyloxyethylidene)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepane(10)

t-Butyldiphenylsilyl chloride (275 mg, 0.001 mol) in dimethylformamide(1 ml) and imidazole (68 mg, 0.001 mol) are added to a solution of(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-hydroxyethylidene)-2-methyl-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepane(275 mg, 0.001 mol) in dimethylformamide (3 ml) at 23° C. in a nitrogenatmosphere. The mixture is stirred for 18 hours at 23° C. and thenpoured into a saturated sodium chloride solution (20 ml) and extractedwith ether (5×50 ml). The ether phases are combined, dried (MgSO₄) andevaporated in vacuo to give 890 mg of a yellow oil. This material ischromatographed on SilicAR CC-7 (5 g, Mallinckrodt) in hexane. Elutionwith 7.5% ethyl acetate/hexane gives(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-t-butyldiphenylsilyloxyethylidene)-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepaneas a light yellow oil.

EXAMPLE 9(2S*,3R*)-3-t-Butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-oxepane(11)

A solution of(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-t-butyldiphenylsilyloxyethylidene)2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepane(832 mg, 0.001 mole), methanol (4 ml) and acetic acid (4 ml) is heatedto 40° C. and stirred and maintained at this temperature for 18 hoursunder a nitrogen atmosphere. The reaction mixture is cooled and themethanol and acetic acid are evaporated under reduced pressure. Themixture is diluted with water (10 ml) and the aqueous layer is extractedwith ether (3×50 ml). The combined organic layers are washed withsaturated sodium bicarbonate, water and saturated sodium chloride anddried (MgSO₄). The solvents are removed under reduced pressure and thecrude product (780 mg) is chromatographed on SilicAR CC-7 (9 g,Mallinckrodt) in hexane. Elution with 15% ethyl acetate/hexane gives(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-oxepaneas a colorless oil.

EXAMPLE 10(2S*,3R*)-3-t-Butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-methyl-2-(4'-methyl-5'-oxopentyl)-oxepane(12)

A pyridine chromium trioxide solution [pyridine (0.96 g, 0.012 mol) andchromium trioxide (0.600 g, 0.006 mole)] is prepared in dry methylenechloride (20 ml) at 0° C. in a nitrogen atmosphere. The cooling bath isremoved and celite (3 g) is added at 15° C. The solution is cooled to 0°C. and treated with(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-oxepane(0.743 g, 0.001 mole) in methylene chloride (5 ml). After 1 hour themixture is filtered and the celite cake is washed with methylenechloride (10×10 ml). The organic phases are combined, washed withsaturated sodium bicarbonate (2×50 ml), saturated sodium chloride anddried (MgSO₄). The solvent is removed at reduced pressure and theresulting crude product is chromatographed on SilicAR CC-7 (10 g,Mallinckrodt). Elution with 15-20% ethyl acetate/hexane gives (2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2'-t-butyldiphenylsilyloxyethylidene)-2-methyl-2-(4'-methyl-5'-oxopentyl)-oxepaneas a yellowish oil.

EXAMPLE 11(2S*,3R*)-3-t-Butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-5'-hydroxy-6'-nonynyl)-2-methyloxepane(13)

A solution of ethyl bromide (229 mg, 2.1 mmol) in anhydroustetrahydrofuran (3 ml) is added over 15 minutes to a suspension ofmagnesium turnings (50 mg, 2 mmoles) in tetrahydrofuran (3 ml). Afterthe magnesium has dissolved, the solution is cooled to 0° C. and asolution of 3-methyl-1-butyne (142 mg, 2.1 mmol) in anhydroustetrahydrofuran (5 ml) is added over a period of 5 minutes. Thissolution is added dropwise via cannula over 10 minutes to a solution of(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-methyl-2-(4'-methyl-5'-oxopentyl)oxepane(0.700 g, 1 mmole) in tetrahydrofuran (4 ml). The mixture is stirred for0.5 hours, quenched with water (10 ml), poured into water, saturatedsodium chloride, dried (MgSO₄) and evaporated in vacuo to give 800 mg ofa yellow oil. The oil is chromatographed on SilicAR CC-7 (4 g,Mallinckrodt) in hexane. Elution with 7-10% ethyl acetate/hexane gives(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-5'-hydroxy-6'-nonynyl)-2-methyloxepane as a colorlessoil.

EXAMPLE 12(2S*,3R*)-3-t-Butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(2',8'-dimethyl-5'-hydroxy-6'-nonenyl)-2-methyloxepane(14)

A solution of(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylene)-2-(4',8'-dimethyl-5'-hydroxy-6'-nonynyl)-2-methyloxepane(0.81 g, 0.001 mol) in anhydrous tetrahydrofuran (5 ml) is addeddropwise to a suspension of lithium aluminum hydride (76.5 mg, 0.002mol) in anhydrous tetrahydrofuran (5 ml) under nitrogen. The mixture isrefluxed for 3 hours and then stirred at room temperature for 18 hours.Quenching is accomplished by the successive addition of water (0.3 ml),15% aqueous sodium hydroxide (0.3 ml) and water (0.9 ml). The mixture isfiltered and the solids are washed with ether. The organic layer iswashed with water, saturated sodium chloride, dried (MgSO₄) andevaporated to give 790 mg of a clear colorless oil. The oil ischromatographed on SilicAR CC-7 (10 g, Mallinckrodt). Elution with 10%ethyl acetate/hexane gives(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-5'-hydroxy-6'-nonenyl)-2-methyloxepane as a colorless oil.

EXAMPLE 13(2S*,3R*)-3-t-Biutyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-6'-nonenyl-5'-oxo)-2-methyloxepane(15)

Chromium trioxide (0.600 g, 0.006 mole) is added to a solution ofpyridine (0.96 g, 0.012 mol) in anhydrous methylene chloride (20 ml) of0° C. under nitrogen. The mixture is allowed to warm to room temperatureand celite (3 g) is added. The solution is cooled to 0° C. and(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-5'-hydroxy-6'-nonenyl)-2-methyloxepane(0.810 mg, 0.001 mole) in methylene chloride (10 ml) is added. After 1hour, the mixture is filtered and the solids are washed with methylenechloride. The organic phases are combined, washed with saturated sodiumbicarbonate (2×50 m), saturated copper sulfate, water, saturated sodiumchloride and dried (MgSO₄). The solvent is removed at reduced pressureand the resulting crude product (700 mg) is chromatographed on SilicARCC-7 (10 g, Mallinckrodt). Elution with 10-12% ethyl acetate/hexanegives (2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-6'-nonenyl-5'-oxo)-2-methyloxepaneas a colorless oil

EXAMPLE 14(2S*,3R*)-3-t-Butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-7'-nonenyl-5'-oxo)-2-methyloxepane(16)

A solution of(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-6'-nonenyl-5'-oxo)-2-methyloxepane(179 mg, 0.22×10⁻³ mole) in tertiary butanol (3 ml) is added to asolution of potassium t-butoxide [K(87 mg, 2.21×10⁻³ mole) and t-BuOH (7ml)] in a nitrogen atmosphere. The solution is stirred for 16 hours andquenched with 10% acetic acid (10 ml). The solution is then poured intosaturated sodium bicarbonate (50 ml) and extracted with ether (5×25 ml).The ether phases are combined, washed with water (2×25) and saturatedsodium chloride (25 ml), dried (MgSO₄) and the ether is removed underreduced pressure to give(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-7'-nonenyl-5'-oxo)-2-methyloxepaneas a light yellow oil.

EXAMPLE 15(2S*,3R*)-3-t-Butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-5'-hydroxy-7-nonenyl)-2-methyloxepane(17)

To a solution of(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-7'-nonenyl-5'-oxo)-2-methyloxepane(0.804 g, 0.001 mol) in absolute EtOH (20 ml) at 0° C. is added asolution of sodium borohydride (38 mg, 0.001 mol) in absolute EtOH (10ml) over a period of 30 minutes. The resulting yellow solution isstirred at 0° C. for 5 hours. The ethanol is removed by distillation atreduced pressure, the residue is poured into saturated sodium chloridesolution (25 ml) and the product is extracted with chloroform (3×50 ml).The organic layers are combined, dried (MgSO₄) and evaporated in vacuo.The crude product is chromatographed on SilicAR CC-7 (10 g,Mallinckrodt). Elution with 15% ethyl acetate/hexane gives(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4',8'-dimethyl-5'-hydroxy-7-nonenyl)-2-methyloxepane(790 mg, 95 %) as a colorless oil.

EXAMPLE 16(2S*,3R*)-3-t-Butyldiphenylsilyloxy-6(2"-t-butyldiphenylsilyloxyethylidene)-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7-nonenyl]-2-methyloxepane(18)

A mixture of the alcohol(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-(4'-8'-dimethyl-5'-hydroxy-7-nonenyl)-2-methyloxepane(0.806 g, 0.001 mol), dihydropyran (168 mg, 0.002 mol) andp-toluenesulfonic acid (25 mg) in anhydrous ether (10 ml) is stirred at23° C. under a nitrogen atmosphere for 18 hours. The mixture is dilutedwith ether (100 ml), washed with saturated sodium bicarbonate, water,and saturated sodium chloride, dried (MgSO₄) and evaporated underreduced pressure to give the crude product. The crude product ischromatographed on SilicAR CC-7 (5 g, Mallinckrodt) in hexane. Elutionwith ethyl acetate/hexane gives(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyloxyethylidene)-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7-nonenyl]-2-methyloxepaneas a colorless oil (0.880 g, 98%).

EXAMPLE 17(2S*,3R*)-6Z-(2"-Hydroxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7'-nonenyl]-oxepan-3-ol(19) and(2S*,3R*)-6E-(2"-Hydroxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7'-nonenyl]-oxepan-3-ol(20)

Compound(2S*,3R*)-3-t-butyldiphenylsilyloxy-6-(2"-t-butyldiphenylsilyoxyethylidene)-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7-nonenyl]-2-methyloxepane(0.890 g, 0.001 mol) is dissolved in tetrahydrofuran (20 ml) undernitrogen and treated with 0.8 M tetrabutylammonium fluoride intetrahydrofuran (30 ml). The solution is stirred for 2 hours. Thesolvent is evaporated under reduced pressure, diluted with water (20 ml)and the aqueous layer extracted with ether (5×100 ml). The organiclayers are combined, washed with saturated sodium chloride (25 ml),dried (MgSO₄) and evaporated in vacuo to give a slightly yellow oil(0.590 g). The material is chromatographed on silica gel (16 g, Baker)in hexane. Elution with 22% to 24% ethyl acetate/hexane gives(2S*,3R*)-6Z-(2"-hydroxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7'-nonenyl]-oxepan-3-ol(155 mg): nmr (CDCl₃) δ 0.85 (d, 3H, J=6 Hz, --CH--CH₃), 1.18 (s, 3H,CH₃), 2.2 (m, 4H, ##STR18## Further elution with 24% to 26% ethylacetate gives (2S*,3R*)-6E-(2"-hydroxyethylidene)-2-methyl-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7'-nonenyl]-oxepan-3-ol(222 mg), nmr (CDCl₃) δ 0.9 (d, 3H, J=6 Hz, ##STR19## 1.15 (s, 3H, CH₃),4.18 (m, 4H, ##STR20## 4.65 (broad s, 1H, ##STR21## 5.30 (m, 2H,--C═CH--CH₂ OH and ##STR22##

EXAMPLE 18(2S*,3R*)-3-Acetoxy-6Z-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-(tetrahydropyran-2'-yloxy)-7'-nonenyl]-oxepane(21)

A solution of(2S*,3R*)-6Z-(2"-hydroxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7'-nonenyl]-oxepan-3-ol(0.172 g, 0.00040 mole) in pyridine (2 ml) and acetic anhydride (0.2 ml)is stirred under nitrogen at 24° C. for 18 hours. The reaction mixtureis then poured into water and stirred for 1.5 hours. The suspension isextracted with ether (5×50 ml) and the ether extracts washed with water,saturated copper sulfate solution, dried (MgSO₄) and evaporated in vacuoto give 170 mg of a yellowish oil. The oil is chromatographed on silicagel (2 g, Baker) in hexane. Elution with 10% ethyl acetate/hexane gives(2S*,3R*)-3-acetoxy-6Z-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7'-nonenyl]-oxepane(166 mg, 82%): nmr (CDCl₃) δ 0.9 (d, 3H, J= 6 Hz, ##STR23## 1.20 (s, 3H,##STR24## 2.10 (s, 6H, ##STR25## 3.40 (m, 1H, ##STR26## centered at 4.42(m, 6H, ##STR27##

EXAMPLE 19(2S*,3R*)-3-Acetoxy-6Z-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-hydroxy-7'-nonenyl]-oxepane(22)

A solution of(2S*,3R*)-3-acetoxy-6Z-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7'-nonenyl]-oxepane(80 mg, 0.000157 moles) in acetic acid/water/tetrahydrofuran 20:10:1 (3ml) is stirred under nitrogen at 40° C. for 4 hours. The reactionmixture is cooled and poured into ether (50 ml) and the ether washedwith saturated bicarbonate (50 ml). The ether phase is separated and theaqueous phase is extracted with ether (3×25 ml). The ether phases arecombined and dried (MgSO₄). The solvents are removed under reducedpressure and the crude product (72 mg) is chromatographed on silica gel(1.1 g. Baker) in hexane. Elution with 8% ethyl acetate/hexane gives(2S*,3R*)-3-acetoxy-6Z-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5-hydroxy-7'-nonenyl]-oxepane(61 mg, 90%): ir (neat) 3400 (OH), 1724 cm⁻ 1 (OAc); nmr (CDCl₃) δ 0.90(d, J=6 Hz, ##STR28## 2.06 (s, 6H, 2-OCOCH₃), 3.4 (m, 1H, CH₂--CH--OH--CH--), 4.3 (s, 2H, ##STR29## 4.5 (d, 2H, --C═CH--CH₂ --OAc),4.7 (m, 1H, ##STR30##

EXAMPLE 20(2S*,3R*)-3-Acetoxy-6Z-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-7'-nonenyl-5'-oxo]-oxepane(23)

A pyridine-chromium trioxide solution [pyridine (345 mg, 0.00385 mole)and chromium trioxide (192 mg, 0.00192 mole)] is prepared in drymethylene chloride (27 ml) at 0° C. in a nitrogen atmosphere. Thecooling bath is removed and celite (1.5 g) is added at 10° C. Thesolution is cooled to 0° C. and(2S*,3R*)-3-acetoxy-6Z-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-hydroxy-7'-nonenyl]-oxepane(136 mg, 0.00032 mole) is added. After 1 hour, the mixture is filteredand the celite cake is washed with methylene chloride (10×10 ml). Theorganic phases are combined, washed with saturated sodium bicarbonate(2×25 ml), saturated sodium chloride and dried (MgSO₄). The solvent isremoved at reduced pressure and the resulting crude product (140 mg) ischromatographed on silica gel (1.5 g, Baker) in hexane. Elution with 8%ethyl acetate/hexane gives a colorless oil(2S*,3R*)-3-acetoxy-6Z-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-7'-nonenyl-5'-oxo]-oxepane(57) (100 mg, 84%): ir (neat) 1740 (OAc), 1710 cm⁻¹ (CO), nmr (CDCl₃) δ1.0 (d, 3H, J=6 Hz, ##STR31## 1.16 (s, 3H, CH₃), 2.05 (s, 6H, 2--COCH₃),3.18 (m, 2H, ##STR32## 4.4 (m, 2H, --C═CH--CH₂ --OAc), 4.62 (m, 1H,##STR33##

EXAMPLE 21(2S*,3R*)-3-Acetoxy-6E-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7'-nonenyl]-oxepane(25)

A solution of(2S*,3R*)-6E-(2"-hydroxyethylidene)-2-methyl-2-[4',8'-dimethyl-5-(tetrahydropyran-2"-yloxy)-7'-nonenyl]-oxepan-3-ol(252 mg, 0.000594 mole) in pyridine (3 ml) and acetic anhydride (0.3 ml)is stirred under nitrogen at 24° C. for 18 hours. The reaction mixtureis then poured into water and stirred for 1.5 hours. The suspension isextracted with ether (5×50 ml) and the ether extracts are washed withwater, saturated copper sulfate solution, dried (MgSO₄) and evaporatedin vacuo to give a yellowish oil (300 mg). The oil is chromatographed onsilica gel (3 g, Baker) in hexane. Elution with 10% ethyl acetate/hexanegives(2S*,3R*)-3-acetoxy-6E-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7'-nonenyl]-oxepane(283 mg, 96%): nmr (CDCl₃) δ 0.80 (d, J=6 Hz, 3H, --CH--CH₃), 0.90 (d,J=6 Hz, 3H, ##STR34## 2.01 (s, 6H, 2-OCOCH₃), 4.10 (s, 2H, ##STR35##

EXAMPLE 22(2S*,3R*)-3-Acetoxy-6E-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-hydroxy-7'-nonenyl]-oxepane(26)

A solution of(2S*,3R*)-3-acetoxy-6E-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-(tetrahydropyran-2"-yloxy)-7'-nonenyl]-oxepane(280 mg, 0.00055 mole), in acetic acid/water/tetrahydrofuran 20:10:1 (5ml) is stirred under nitrogen at 40° C. for 4 hours. The reactionmixture is cooled and poured into ether (50 ml) and the ether mixture iswashed with saturated sodium bicarbonate (50 ml). The ether phase isseparated and the aqueous phase is extracted with ether (4×50 ml). Theether phases are combined and dried (MgSO₄). The solvents are removedunder reduced pressure and the crude product (230 mg) is chromatographedon silica gel (2.3 g, Baker) in hexane. Elution with 8% ethylacetate/hexane gives(2S*,3R*)-3-acetoxy-6E-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-hydroxy-7'-nonenyl]-oxepane(196 mg, 84%): nmr (CDCl₃) δ 0.90 (d, J=6 Hz, 3H, ##STR36## 1.19 (s, 3H,CH₃), 2.05 (s, 6H, 2-O-COCH₃), 3.40 (s, 1H, --CH--OH), 4.10 (s, 2H,

EXAMPLE 23(2S*,3R*)-3-Acetoxy-6E-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-7'-nonenyl-5'-oxo]-oxepane(27)

A solution of pyridine (440 mg, 0.00558 mole) and chromium trioxide (279mg, 0.00279 mole) in methylene chloride (25 ml) in a nitrogen atmosphereis stirred for 45 minutes at 0° C. Celite (2 g) is added followed by(2S*,3R*)-3-acetoxy-6E-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-hydroxy-7'-nonenyl]-oxepane(197 mg, 0.000465 mole) in methylene chloride (25 ml). The mixture isstirred for 90 minutes at 23° C. The mixture is then filtered and thecelite cake is washed with methylene chloride (10×10 ml). The filtrateand the washings are combined and the methylene chloride extracts arewashed with sodium bicarbonate, water and saturated sodium chloride,dried (MgSO₄) and evaporated in vacuo. The crude product (201 mg) ischromatographed on silica gel (3 g, Baker) in hexane. Elution with 8%ethyl acetate/hexane gives(2S*,3R*)-3-acetoxy-6E-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-7'-nonenyl-5'-oxo]-oxepaneas a colorless oil (173 mg, 88%): ir (neat) 1710 (CO), 1740 (OAc) cm⁻¹,nmr (CDCl₃) δ1.0 (d, 3H, J=6 Hz, --CHCH₃), 1.18 ##STR37##

EXAMPLE 24(2S*,3R*)-6E-(2"-Hydroxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-oxo-7'-nonenyl]-oxepan-3-ol(28)

A solution of(2S*,3R*)-3-acetoxy-6E-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-7'-nonenyl-5'-oxo]-oxepane(173 mg, 0.000410 mole), tetrabutylammonium hydroxide in methanol (40%solution, 1 ml), water (4 ml) and tetrahydrofuran (4 ml) at 25° C. in anitrogen atmosphere is stirred for 24 hours. The solution is thendiluted with saturated sodium chloride (50 ml) and the aqueous layer isextracted with ethyl acetate (5×50 ml). The combined organic layers aredried (MgSO₄) and evaporated in vacuo. The crude product (170 mg) ischromatographed on silica gel (3.5 g, Baker) in chloroform. Elution withchloroform gives(2S*,3R*)-6E-(2"-hydroxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-oxo-7'-nonenyl]-oxepan-3-olas a colorless oil (110 mg, 80%): ir (neat) 3448 (OH) 1709 (CO) cm⁻¹,5.41 (m, 2H, --C═CH--CH₂ OH and ##STR38## 1.64 [d, 6H, --HC═C--(CH₃)₂ ],1.18 (s, 3H, ##STR39## 1.05 (d, J=6 Hz, 3H, --CH═CH₃); Mass spectrumm/e, 320 (M-18), 302 (M-2H₂ O), 251, 233, 141, 125, 113, 97, 95, 81, 69.

EXAMPLE 25(2S*,3R*)-6Z-(2"-Hydroxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-oxo-7'-nonenyl]-oxepan-3-ol(24)

A solution of(2S*,3R*)-3-acetoxy-6Z-(2"-acetoxyethylidene)-2-methyl-2-[4',8'-dimethyl-7'-nonenyl-5'-oxo]-oxepane(100 mg, 0.000236 mole), tetrabutylammonium hydroxide in methanol (40%solution, 1 ml), water (4 ml) and tetrahydrofuran (4 ml) at 25° C. in anitrogen atmosphere is stirred for 24 hours. The solution is dilutedwith saturated sodium chloride (50 ml) and the aqueous layer isextracted with ethyl acetate (5×50 ml). The combined organic layers aredried (MgSO₄) and evaporated in vacuo. The crude product (210 mg) ischromatographed on silica gel (1.5 g, Baker) in chloroform. Elution withchloroform gives(2S*,3R*)-6Z-(2"-hydroxyethylidene)-2-methyl-2-[4',8'-dimethyl-5'-oxo-7'-nonenyl]-oxepan-3-olas a colorless oil (65 mg, 81%): ir (neat) 3448 (OH), 1709 (CO) cm⁻¹,nmr (CDCl₃) δ 5.41 (m, 2H, ##STR40## Mass spectrum m/e, 320 (M-18), 302(M--2H₂ O), 251, 233, 141, 125, 113, 97, 95, 81, 69.

Preparation of starting material:

EXAMPLE A (1R*,9R*)-1-Acetoxy-6,6-ethylenedioxy-9-methyl-4(10)-octalin

A mixture of (1R*,9R*)-1-acetoxy-9-methyl-5(10)-octalin-6-one (23 g,0.103 mol), ethylene glycol (100 ml) and p-toluenesulfonic acid (100 mg)in benzene (700 ml) is refluxed for 16 hours using a Dean-Starkapparatus. The cooled solution is diluted with water (500 ml) and ether(500 ml). The organic layer is separated and the aqueous layer isextracted with ether (2×250 ml). The combined organic layers are washedwith saturated sodium bicarbonate (4×200 ml), water (2×200 ml) andsaturated sodium chloride, and dried (MgSO₄). The solvents are removedat reduced pressure and the crude product (26 g) is chromatographed onSilicAR CC-7 (350 g, Mallinckrodt) in hexane. Elution with 7-10% ethylacetate/hexane gives(1R*,9R*)-1-acetoxy-6,6-ethylenedioxy-9-methyl-4(10)-octalin as acolorless oil (22 g, 80%): ir (neat) 1724 cm⁻¹ (OAc); nmr (CDCl₃) δ 1.18(s, 3H, CH₃), 2.02 (s, 3H, --OCO--CH₃), 3.98 (s, 4H, ketal), 4.82 (m,1H, ##STR41## 5.35 (m, 1H, ##STR42##

EXAMPLE B (1R*,9R*)-6,6-Ethylenedioxy-1-hydroxy-9-methyl-4(10) -octalin

A solution of(1R*,9R*)-1-acetoxy-6,6-ethylenedioxy-9-methyl-4(10)-octalin (22 g,0.0827 mol) and saturated potassium carbonate (100 ml) in methanol (800ml) and water (100 ml) at 25° C. in a nitrogen atmosphere is stirred for48 hours. The methanol is evaporated under reduced pressure, dilutedwith water (500 ml) and the aqueous layer is extracted with chloroform(2×700 ml). The combined organic layers are washed with water (3×600 ml)and saturated sodium chloride (3×700 ml), dried (MgSO₄) and evaporatedin vacuo. The crude product (19 g) is chromatographed on SilicAR CC-7(234 g, Mallinckrodt) in hexane. Elution with 20% ethyl acetate/hexanegives (1R*,9R*)-6,6-ethylenedioxy-1-hydroxy-9-methyl-4(10)-octalin as acolorless oil (16.6 g, 87%): ir (KBr) 3546 cm⁻¹ (OH): nmr (CDCl₃) δ 1.10(s, 3H, CH₃), 3.60 (m, 1H, ##STR43## 3.98 (s, 4H, ketal), 5.27 (m, 1H,##STR44##

EXAMPLE C (1R*,9R*)-1-Benzyloxy-6,6-ethylenedioxy-9-methyl-4(10)-octalin

To a suspension of sodium hydride (18.7 g, 0.780 mol, 50% dispersion inoil, previously washed with hexane) in benzene (1200 ml) is added thealcohol (1R*,9R*)-6,6-ethylenedioxy-1-hydroxy-9-methyl-4(10)-octalin(87.37 g, 0.390 mol) in benzene (100 ml) in a nitrogen atmosphere. After0.5 hours, benzylbromide (115.0 g, 0.672 mol) in benzene (100 ml) isadded. The mixture is refluxed for 24 hours, cooled and poured intosaturated sodium chloride (1000 ml). The aqueous layer is extracted withdiethyl ether (3×250 ml). The organic phases are combined, dried (MgSO₄)and the solvents are removed under reduced pressure. The crude product(137.1 g) is chromatographed on SilicAR CC-7 (550 g, Mallinckrodt) inhexane. Elution with 5-10% ethyl acetate/hexane gives(1R*,9R*)-1-benzyloxy-6,6-ethylenedioxy-9-methyl-4(10)-octalin as aclear colorless oil (111.7 g, 91%): nmr (CDCl₃ ) δ 1.20 (s, 3H, CH₃),3.36 (m, 1H, ##STR45## 3.98 (s, 4H, ketal), 4.56 (d of d, J=10 Hz, 2H,Ph--CH₂ --O--), 5.23 (broad s, 1H, ##STR46## 7.23 (s, 5H, aromatic).

EXAMPLE D (1R*,9R*)-1-Benzyloxy-9-methyl-5(10)-octalin-6-one

A mixture of(1R*,9R*)-1-benzyloxy-6,6-ethylenedioxy-9-methyl-4(10)-octalin (111.7 g,0.355 mol), methanol (400 ml) and acetic acid (400 ml) is refluxed for18 hours under a nitrogen atomsphere. The reaction mixture is cooled andthe methanol and acetic acid evaporated under reduced pressure. Themixture is diluted with water (800 ml) and the aqueous layer extractedwith ether (3×1000 ml). The combined organic layers are washed withsaturated sodium bicarbonate, water and saturated sodium chloride anddried (MgSO₄). The solvents are removed under reduced pressure and thecrude product (94.2 g) is chromatographed on silicAR CC-7 (900 g,Mallinckrodt) in hexane. Elution with 10% ethyl acetate/hexane gives(1R*,9R*)-1-benzyloxy-9-methyl-5(10)-octalin-6-one as a colorless oil(85.4 g, 89%): ir (neat) 1660, 1612 cm⁻¹ (α,β-unsaturated CO): nmr(CDCl₃) δ 1.22 (s, 3H, CH₃), 3.16 (m, 1H, --CH--OCH₂ Ph), 4.56 (d of d,J=10 Hz, 2H, Ph--CH₂ --O--), 5.78 (broad s, 1H, >C--CH═CO--), 7.30 (s,5H, aromatic).

EXAMPLE E (1R*,9R*)-1-Benzyloxy-9-methyl-5(10)-oxido-octalin-6-one

To a solution of (1R*,9R*)-1-benzyloxy-9-methyl-5(10)-octalin-6-one(81.2 g, 0.300 mol) in methanol (600 g) cooled to 0° C. under nitrogenis added with stirring 30% hydrogen peroxide (136 g, 1.2 mol). Whilemaintaining the temperature at 0° C., 6 N sodium hydroxide (30 ml) isadded dropwise over 20 minutes. After the addition is complete, thereaction mixture is stirred for 4 hours at 25° C. The reaction mixtureis then poured into saturated sodium chloride (2000 ml) and extractedwith diethyl ether (7×1000 ml). The combined organic layers are washedwith water and dried (MgSO₄). The solvents are removed under reducedpressure to give a mixture of epoxides(1R*,9R*)-1-benzyloxy-9-methyl-5(10)oxido-octalin-6-one (60 g, 70%): ir(neat) 1724 cm⁻¹ (CO); nmr (CDCl₃) δ 1.08 (s, 3H, CH₃), 1.18 (s, 3H,CH₃), 2.82 (s, 1H, --CO--CH--CO--), 3.00 (s, 1H, ##STR47## 4.4 (d of d,J=10 Hz, 2H, Ph--CH₂ O--), 7.20 (s, 5H, aromatic).

EXAMPLE F (2S*,3R*)-3-Benzyloxy-2-(3'-butynyl)-2-methylcyclohexanone

To a stirred solution of(1R*,9R*)-1-benzyloxy-9-methyl-5(10)-oxido-octalin-6-one (27.8 g, 0.0965mol) in methylene chloride (500 ml) and acetic acid (350 ml) at 0° C.under nitrogen is added p-toluenesulfonylhydrazide (18.2 g, 0.097 mol)in one portion. Stirring is continued at 0° C. for 3 hours followed by19 hours at 25° C. The reaction mixture is poured into water (1000 ml)and the methylene chloride layer is separated. The aqueous layer isextracted with methylene chloride (2×500 ml). The combined organiclayers are washed with water, saturated sodium bicarbonate (2×750 ml),water, saturated sodium chloride and dried (MgSO₄). The solvents areremoved at reduced pressure to give a slightly yellow oil (27.5 g,100%). The crude product is chromatographed on SilicAR CC-7 (600 g,Mallinckrodt) in hexane. Elution with 10% ethyl acetate/hexane gives(2S*,3R*)-3-benzyloxy-2-(3'-butynyl)-2-methylcyclohexanone: ir (neat)2132 (C.tbd.C), 1704 cm⁻¹, (CO); nmr (CDCl₃) δ 1.20 (s, 3H, CH₃), 2.38(m, 1H, --C.tbd.CH), 3.50 (m, 1H, ##STR48## 4.56 (d of d, J=10 Hz, 2H,Ph--CH₂ --O--), 7.25 (s, 5H, aromatic).

EXAMPLE G(2S*,3R*)-3-Benzyloxy-2-(3'-butynyl)-1,1-ethylenedioxy-2-methylcyclohexane

A mixture of (2S*,3R*)-3-benzyloxy-2-(3'-butynyl)-2-methylcyclohexanone(27.5 g, 0.102 mol), ethylene glycol (100 ml) and p-toluenesulfonic acid(1 g) in benzene (600 ml) is refluxed for 20 hours using a Dean-Starkapparatus. The cooled solution is washed with saturated sodiumbicarbonate (3×250 ml) and water (2×250 ml) and dried (MgSO₄). Thesolvent is removed at reduced pressure and the crude product (30.3 g) ischromatographed on SilicAR CC-7 (600 g, Mallinckrodt) in hexane. Elutionwith 3% ethyl acetate/hexane gives(2S*,3R*)-3-benzyloxy-2-(3'-butynyl)-1,1-ethylenedioxy-2-methylcyclohexaneas a colorless oil (23.9 L g, 75%): ir (neat) 2126 cm⁻¹ (C.tbd.C); nmr(CDCl₃) δ 1.06 (s, 3H, CH₃), 2.30 (m, 1H, --C.tbd.CH), 3.41 (m, 1H,##STR49## 3.98 (s, 4H, ketal), 4.50 (d of d, J=10 Hz, 2H, Ph--CH₂--O--), 7.20 (s, 5H, aromatic).

EXAMPLE H(2S*,3R*)-3-Benzyloxy-1,1-ethylenedioxy-2-(4'-hydroxybutyl)-2-methylcyclohexane

To a stirred solution of 9-borabicyclononane (37.1 g, 0.304 mol) in drytetrahydrofuran (1200 ml) maintained at 0° C. in a nitrogen atomsphereis added a solution of(2S*,3R*)-3-benzyloxy-2-(3'-butynyl)-1,1-ethylenedioxy-2-methylcyclohexane(45.2 g, 0.144 mol) in dry tetrahydrofuran (300 ml). After the additionis complete, the mixture is stirred for 5 hours at 25° C. At the end ofthis period, the reaction mixture is cooled to 0° C. and 3 N sodiumhydroxide (140 ml, 0.42 mol) followed by 30% hydrogen peroxide (159.6 g,1.4 mol) are added while maintaining the temperature at 0° C. After theaddition is complete, the mixture is stirred for 1 hour at 25° C. Themixture is then diluted with saturated sodium chloride (2000 ml) andextracted with ether (6×100 ml). The ether phases are combined, dried(MgSO₄) and the solvents are removed under reduced pressure. The crudeproduct (101.9 g) is chromatographed on SilicAR CC-7 (1000 g,Mallinckrodt) in hexane. Elution with 25% ethyl acetate/hexane gives(2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-(4'-hydroxybutyl)-2-methylcyclohexaneas a colorless oil (42.3 g, 88%): ir (neat) 3448 cm⁻¹ (OH), nmr (CDCl₃)δ1.02 (s, 3H, CH₃), 3.92 (s, 4H, ketal), 4.50 (d of d, J=10 Hz, 2H,--O--CH₂ Ph), 7.26 (s, 5H, aromatic).

EXAMPLE I (2S*,3R*)-3-Benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxobutyl)-cyclohexane

A pyridine-chromium trioxide solution [C₅ H₅ N (120 g, 1.524 mol) andCrO₃ (76.2 g, 0.762 mol)] is prepared in dry methylene chloride (2700ml) at 0° C. in a nitrogen atmosphere. The cooling bath is removed andcelite (300 g) is added at 15° C. At 23° C., the alcohol (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-(4'-hydroxybutyl)-2-methylcyclohexane(42.3 g, 0.127 mol) in methylene chloride (300 ml) is added. After 1hour, the mixture is filtered and the celite cake is washed withmethylene chloride (10×100 ml) and the solvent is removed at reducedpressure. The residue is diluted with ether (750 ml) and filtered. Thesolvent is removed at reduced pressure and the resulting crude product(46.0 g) is chromatographed on SilicAR CC-7 (1000 g, Mallinckrodt) inhexane. Elution with 25% ethyl acetate/hexane gives (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxobutyl)-cyclohexane as acolorless oil (25.4 g, 60%): ir (neat) 1718 cm⁻¹ (CHO); nmr (CDCl₃)δ1.02 (s, 3H, --CH₃), 3.90 (s, 4H, ketal), 4.46 (d of d, J=10 Hz, 2H,--O--CH₂ Ph), 7.23 (s, 5H, aromatic), 9.63 (t, 1H, --CHO).

EXAMPLE J (2S*,3R*)-3-Benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexane

Methyllithium (63.3 ml, 0.0918 mol, 1.45 M in ether) is added dropwiseto a solution of the aldehyde, (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxobutyl)-cyclohexane(25.4 g, 0.0765 mol) in ether (1000 ml) at 0° C. in a nitrogenatmosphere. The cooling bath is removed and the mixture is stirred for0.5 hours at ambient temperature. The mixture is then poured into a coldsaturated sodium chloride solution (500 ml). The ether phase isseparated and the aqueous phase is extracted with ether (3×100 ml). Theether phases are combined, dried (MgSO₄) and the solvent is removed atreduced pressure. The crude product (27.1 g) is chromatographed onSilicAR CC-7 (300 g, Mallinckrodt) in hexane. Elution with 10% ethylacetate/hexane gives (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexaneas a colorless oil (25.8 g, 97%).

EXAMPLE K (2S*,3R*)-3-Benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxopentyl)-cyclohexane

A solution of pyridine (70.3 g, 0.89 mol) and chromium trioxide (44.5 g,0.445 mol) in methylene chloride (1.8 l) in a nitrogen atmosphere isstirred for 45 minutes. Celite (180 g) is added followed by (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexane(25.8 g, 0.074 mol) in methylene chloride (100 ml). The mixture isstirred for 90 minutes at 23° C. The mixture is then filtered and thecelite cake is washed with methylene chloride (10×200 ml). The filtrateand washings are combined and the solvents are removed under reducedpressure to give a dark oil, which is diluted with ether (750 ml) andfiltered. The ether phase is dried (MgSO₄) and the solvents are removedat reduced pressure. The crude product (21 g) is chromatographed onSilicAR CC-7 (300 g, Mallinckrodt) in hexane. Elution with 6% ethylacetate/hexane gives (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxopentyl)-cyclohexaneas a clear colorless oil (15.7 g, 61%): ir (neat) 1712 cm⁻¹ (CO); nmr(CDCl₃)δ 1.06 (s, 3H, --CH₃), 2.04 (s, 3H, ##STR50## 2.30 (m, 2H, --CH₂--CO), 3.50 (m, 1H, ##STR51## 3.98 (s, 4H, ketal), 4.55 (d of d, J=10Hz, 2H, --O--CH₂ Ph), 7.20 (s, 5H, aromatic).

EXAMPLE L (2S*,3R*)-3-Benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-methyl-4'-pentenyl)-cyclohexane

A suspension of sodium hydride (10.9 g, 0.227 mol) in dimethylsulfoxide(250 ml) is heated to 70° C. under a nitrogen atmosphere and stirred for45 minutes. The mixture is cooled to 25° C. andmethyltriphenylphosphonium iodide (91.7 g, 0.227 mol) indimethylsulfoxide (100 ml) is added. The mixture is stirred for 30minutes, (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxopentyl)-cyclohexane(15.7 g, 0.045 mol) in dimethylsulfoxide (50 ml) is added and themixture is heated to 60° C. After 4 hours, the reaction mixture iscooled and added to saturated sodium chloride (1000 ml) and extractedwith ether (5×200 ml). The ether layers are combined, dried (MgSO₄) andthe solvent is removed under reduced pressure. The crude product (24.1g) is chromatographed on SilicAR CC-7 (300 g, Mallinckrodt) in hexane.Elution with 4% ethyl acetate/hexane gives (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-methyl-4'-pentenyl)-cyclohexaneas a light yellow oil (14.3 g, 92%): ir (neat) 1638 cm⁻¹ (C═C), nmr(CDCl₃)δ 1.06 (s, 3H, CH₃), 3.40 (m, 1H, ##STR52## 4.50 (d of d, J=10Hz, 2H, --O--CH₂ Ph), 4.61 (broad s, 2H, ##STR53## 7.30 (s, 5H,aromatic).

EXAMPLE M (2S*, 3R*)-3-Benzyloxy-1,1-l-ethylenedioxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexane

To a solution of 9-borabicyclononane (10.1 g, 0.083 mol) intetrahydrofuran (600 ml) at 0° C. is added a solution of (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-methyl-4'-pentenyl)-cyclohexane(14.3 g, 0.0416 mol) in tetrahydrofuran (150 ml). The cooling bath isremoved and the reaction mixture stirred for 3 hours at 25° C. Thereaction mixture is decomposed at 0° C. by adding 3N sodium hydroxide(33 ml, 0.105 mol) followed by 30% hydrogen peroxide (47.6 g, 0.42 mol).The mixture is poured into saturated sodium chloride (1000 ml) andextracted with ether (5×300 ml). The extracts are combined, dried(MgSO₄) and the solvent is removed under reduced pressure. The crudeproduct (20.1 g) is chromatographed on SilicAR CC-7 (250 g,Mallinckrodt) in hexane. Elution with 8% ethyl acetate/hexane gives(2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexaneas a clear colorless oil (13.9 g, 91%): nmr (CDCl₃)δ 0.86 (d, J=6 Hz,3H, ##STR54## 1.08 (s, 3H, CH₃), 3.42 (broad d, 3H, ##STR55## and OH),3.98 (s, 4H, ketal), 4.52 (d of d, 2H, Ph--CH₂ --O--), 7.20 (s, 5H,aromatic).

EXAMPLE N (2S*,3R*)-3-Benzyloxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexanone

A mixture of (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexane(13.9 g, 0.0384 mol), acetone (150 ml), water (20 ml) and 0.002 Nsulfuric acid (50 ml) is refluxed for 18 hours under a nitrogenatmosphere. The reaction mixture is cooled, the acetone evaporated underreduced pressure and the aqueous layer extracted with ether (3×500 ml).The combined organic layers are washed with saturated sodium bicarbonate(100 ml), saturated sodium chloride (2×200 ml) and dried (MgSO₄). Thesolvents are removed to afford (2S*,3R*)-3-benzyloxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexanone(crude product, 12.2 g, 100%): ir (neat) 3484 (OH), 1709 cm⁻¹ (CO); nmr(CDCl₃)δ 0.88 (d, J=6 Hz, 3H, --CH--CH₃), 1.08 (s, 3H, CH₃), 3.42 (m, 4H, ##STR56## 4.50 (d of d, J=10 Hz, 2H, Ph--CH₂ --O--), 7.2 (s, 5H,aromatic).

EXAMPLE O (2S*,3R*)-3-Benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-cyclohexanone

A mixture of the alcohol (2S*,3R*)-3-benzyloxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexanone(12.2 g, 0.038 mol), dihydropyran (4.8 g, 0.057 mole) andp-toluenesulfonic acid (100 mg) in anhydrous ether (150 ml) is stirredat 24° C. under a nitrogen atmosphere for 18 hours. The mixture is thendiluted with ether (500 ml), washed wth sodium bicarbonate, water andsaturated sodium chloride, dried (MgSO₄) and evaporated in vacuo to give14.3 g of a yellow oil. The oil is chromatographed on SilicAR CC-7 (220g. Mallinckrodt) in hexane. Elution with 5-10% ethyl acetate/hexanegives (2S*,3R*)-3-benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-cyclohexanoneas a colorless oil (14.3 g, 88%): nmr (CDCl₃)δ 0.82 (d, J=6 Hz, --3H,##STR57## 1.10 (s, 3H, CH₃), 4.40 (d of d, J=10 Hz, 2H, --O--CH₂ Ph),4.49 (broad s, 1H, ##STR58## 7.20 (s, 5H, aromatic).

EXAMPLE P (2S*,3R*)-3-Benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-1-oxacycloheptan-7-one

A solution of (2S*,3R*)-3-benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-cyclohexanone(7.6 g, 0.0189 mol), sodium acetate (1.64 g, 0.02 mol),m-chloroperoxybenzoic acid 85% (4.97 g, 0.0246 mole) and distilledmethylene chloride (300 ml) is heated at reflux under a nitrogenatmosphere for 17 hours. The solution is cooled and filtered and thefiltrate is washed with saturated sodium bicarbonate, saturated sodiumchloride and dried (MgSO₄). The solvent is removed under reducedpressure and the crude product (8.2 g) chromatographed on SilicAR CC-7(150 g, Mallinckrodt) in hexane. Elution with 10% ethyl acetate/hexanegives recovered (2S*,3R*)-3-benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-cyclohexanone2.8 g) while 15% ethyl acetate/hexane gives the desired lactone (2S*,3R*)-3-benzyloxy-2-methyl-2-[4'methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-1-oxacycloheptan-7-one(3.5 g, 70% based on the recovery of the starting ketone): nmr (CDCl₃)δ0.95 (d, J=6 Hz, 3H, --CH--CH₃), 1.42 (s, 3H --CH₃), 2.62 (m, 2H,--O--CO--CH₂ --CH₂ --), 4.60 (d of d, J=10 Hz, 2H, --O--CH₂ Ph), 7.22(s, 5H, aromatic).

EXAMPLE Q (2S*,3R*)-Diethyl-[3-benzyloxy-2-methyl-2-(4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl)-3(H),4,5-dihydro oxepinyl]-7-phosphate

To a lithium diisopropylamide solution [prepared from n-butyllithium inhexane (18.2 ml, 0.0285 mol) and diisopropylamine (2.88 g, 0.0285 mol)]in dry tetrahydrofuran (100 ml) with hexamethylphosphoramide (5.1 g,0.0285 mol) cooled to -78° C. is added dropwise a solution of (2S*,3R*)-3-benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-1-oxacycloheptan-7-one(7.9 g, 0.019 mol) in dry tetrahydrofuran (50 ml). After stirring for 45minutes, tetramethylethylenediamine (50 ml) is added followed bydiethylchlorophosphate (4.92 g, 0.0285 mol) in tetrahydrofuran (50 ml).The cooling bath is removed and stirring at room temperature ismaintained for 0.5 hours. The reaction mixture is poured into pH 7buffer (250 ml) and extracted with ether (5×100 ml). The ether phasesare combined, dried (MgSO₄) and the solvent removed under reducedpressure. The crude product (15.3 g) is chromatographed on SilicAR CC-7(200 g, Mallinckrodt) in hexane. Elution with 20% ethyl acetate/hexanegives (2S*,3R*)-diethyl-[3-benzyloxy-2-methyl-2-(4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl)-3(H),4,5-dihydro oxepinyl]-7-phosphate as a clear light yellow oil (8.92 g,85%): nmr (CDCl₃)δ 1.00 (d, J=6 Hz, 3H, --CH--CH₃), 1.20 (s, 3H, --CH₃),4.98 (m, 1H, ##STR59## 7.30 (s, 5H, aromatic).

EXAMPLE R (2S*,3R*)-3-Hydroxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepene

To a freshly distilled solution of ammonia (450 ml) cooled to -78° C. isadded in an argon atmosphere t-butyl alcohol (21.4 g, 0.29 mol). Thecooling bath is removed and (2S*,3R*)-diethyl-[3-benzyloxy-2-methyl-2-(4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl)-3(H),4,5-dihydro oxepinyl]-7-phosphate (8.92 g, 0.0161 mol) intetrahydrofuran (112 ml) is added. Freshly cut sodium metal (2.22 g,0.0966 mol) is added in small pieces at -33° C. The resulting bluesolution is stirred for 0.5 hours and quenched by adding ether (450 ml)followed by water (100 ml). The ammonia is evaporated at roomtemperature and the mixture is poured into pH 7 buffer (1000 ml) andether (250 ml). The ether layer is separated and the water phase isextracted with ether (5×100 ml). The ether phases are combined, washedwith saturated sodium chloride (500 ml), dried (MgSO₄) and the solventis removed under reduced pressure. The crude product (5.2 g) ischromatographed on SilicAR CC-7 (75 g, Mallinckrodt) in hexane. Elutionwith 10% ethyl acetate/hexane gives (2S*,3R*)-3-hydroxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepeneas a clear light yellow oil (2.7 g, 54%): ir (neat) 3481 (OH), 1650 cm⁻¹(O--C═C), nmr (CDCl₃)δ 0.93 (d, J=6 Hz, 3H, ##STR60## 1.22 (s, 3H, CH₃),4.78 (broad s, ##STR61## 4.92 (m, 1H, --O--CH═CH--), 6.01 (m, 1H,--O--CH═CH--).

EXAMPLE S (2S*,3R*)-3-Benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepene

To a suspension of sodium hydride (830 mg, 0.0173 mol) in benzene (50ml) is added (2S*,3R*)-3-hydroxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepene(2.7 g, 0.00865 mol) in benzene (25 ml) in a nitrogen atmosphere. After0.5 hours, benzyl bromide (3.0 g, 0.0173 mol) in benzene (25 ml) isadded. The mixture is refluxed for 16 hours, cooled and poured intosaturated sodium chloride (200 ml). The aqueous layer is extracted withether (5×75 ml). The organic phases are combined, dried (MgSO₄) and thesolvents are removed under reduced pressure. The crude product (3.6 g)is chromatographed on SilicAR CC-7 (75 g, Mallinckrodt) in hexane.Elution with 7% ethyl acetate/hexane gives (2S*,3R*)-3-benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepeneas a clear colorless oil (3.25 g, 93%): nmr (CDCl₃)δ 0.92 (d, J=6 Hz,3H, ##STR62## 1.20 (s, 3H, CH₃), 4.54 (d of d, J=10 Hz, 3H, --O--CH₂ Ph,##STR63## 4.94 (m, 1H, --O--CH═CH--), 6.00 (d, J=6 Hz, 1H,--O--CH═CH--), 7.25 (s, 5H, aromatic).

EXAMPLE T (2S*,3R*)-3-Benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepan-6-ol

To a solution of (2S*,3R*)-3-benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-6-oxepene(3.25 g, 0.0081 mol) in tetrahydrofuran (60 ml) at 0° C. in a nitrogenatmosphere is added diborane (10.8 ml, 0.0108 mol, 1 M solution intetrahydrofuran). The cooling bath is removed and the mixture is stirredfor 2 hours at 25° C. The reaction mixture is then quenched by adding 3N sodium hydroxide (5.4 ml, 0.021 mol) followed by 30% hydrogen peroxide(3.8 g, 3.6 ml, 0.111 mol). The reaction mixture is stirred at 25° C.for 1.5 hours, then poured into saturated sodium chloride (250 ml) andether (150 ml). The ether layer is separated and the aqueous phase isextracted with ether (7×75 ml). The ether phases are combined, dried(MgSO₄) and the solvents are removed at reduced pressure. The crudeproduct (4.1 g) is chromatographed on SilicAR CC-7 (50 g, Mallinckrodt)in hexane. Elution with 25% ethyl acetate/hexane gives (2S*,3R*)-3-benzyloxy-2-methyl-2-[4'-methyl-5'-(tetrahydropyran-2"-yloxy)-pentyl]-oxepan-6-olas a clear colorless oil (2.4 g, 71%): ir (neat) 3500 cm⁻¹ (OH): nmr(CDCl₃)δ 0.92 (d, J=6 Hz, 3H, --CH--CH₃), 7.25 (s, 5H, aromatic); thecompound is a mixture of epimeric alcohols as shown by thin layerchromatography, ethyl acetate/hexane (40:60).

What is claimed is:
 1. The process for the preparation of a compound ofthe formula ##STR64## which comprises reacting a compound of the formula##STR65## with dihydropyran in the presence of p-toluenesulfonic acid toform a compound of the formula ##STR66## reacting the product formedwith tetrabutylammonium fluoride to form a mixture of compounds of theformula ##STR67## separating the compounds in the mixture, and thenreacting compound A with an esterifying agent selected from a loweralkyl anhydride and a lower alkyl halide to form an ester of the formula##STR68## treating the product formed with an acid selected from aceticacid, p-toluenesulfonic acid and camphorsulfonic acid to form an alcoholof the formula ##STR69## treating the alcohol formed with chromiumtrioxide/pyridine to form a ketone of the formula ##STR70## and reactingthe product formed with tetrabutylammonium hydroxide to form a compoundof the formula ##STR71## wherein R is a t-butyldiphenylsilyl group andR₁ is lower alkanoyl having 2-5 carbon atoms.
 2. The process of claim 1wherein the acid is acetic acid.
 3. The process of claim 1 wherein theesterifying agent is acetic anhydride.
 4. The process for thepreparation of a compound of the formula ##STR72## which comprisesreacting a compound of the formula ##STR73## with dihydropyran in thepresence of p-toluenesulfonic acid to form a compound of the formula##STR74## reacting the product formed with tetrabutylammonium fluorideto form a mixture of compounds of the formula ##STR75## separating thecompounds in the mixture, and then reacting compound B with anesterifying agent selected from a lower alkyl anhydride and a loweralkyl halide to form an ester of the formula ##STR76## treating theproduct formed with an acid selected from acetic acid, p-toluenesulfonicacid and camphorsulfonic acid to form an alcohol of the formula##STR77## treating the alcohol formed with chromium trioxide/pyridine toform a ketone of the formula ##STR78## and reacting the product withtetrabutylammonium hydroxide to form a compound of the formula ##STR79##wherein R is a t-butyldiphenylsilyl group and R₁ is lower alkanoylhaving 2-5 carbon atoms.
 5. The process of claim 4 wherein theesterifying agent is acetic anhydride.
 6. The process of claim 4 whereinthe acid is acetic acid.